Alzheimer's disease is critical and may be life threatening for human beings, especially for older people. Demographic data indicate that the percentage of elderly in the population is increasing. Therefore, the threat of Alzheimer's disease is greater and greater. Although there is not a real cure for this disease, there are several drugs for treating Alzheimer's disease, such as tacrine (Parke-Davis), Aricett (Pfizer-Eisai), and Excelon (Novartis).
Tacrine (Tetrahydroaminoacridine or THA, FIG. 11a) functions as the acetylcholinesterase (AChE) inhibitor and was approved by the U.S. Food and Drug Administration (FDA) for treating Alzheimer's disease in recent year. It is marketed as Cognex.RTM. by Parke-Davis. (Crimson, M. L. Ann. Pharmacother. 1994, 28, 744-751). However, there is considerable debate over some drawbacks of tacrine due to its many actions in the CNS and its serious toxicity (Watkins, P. B. et al., J. Am. Med. Assoc. 1994, 271, 992-998).
Therefore, it is very important to design and develop a more selective inhibitor of AChE as opposed to tacrine. Recently, tacrin-1-ol (velnacrine), one of the major metabolites of tacrine, was chosen for clinical trials in Alzheimer's disease (Puri, S. K. et al., J. Clin. Pharmacol. 1990, 30, 948-955). A series of substituted tacrin-1-ols were also developed and found to show more potent anti-AChE activities than did tacrine (Shutske, G. M. et al., J Med. Chem. 1989, 32, 1805-1813). 6-Chloro-tacrin-1-ol was reported to be almost 30 times as potent as tacrine and 6-fluoro-tacrin-1-ol was reported to be slightly more potent than tacrine. Another report revealed that 6-chlorotacrine (1b, FIG. 1) exhibited stronger binding strength toward AChE than did tacrine (Wlodek S. T. et al., Biopolymers 1996, 38, 109-117). In addition to the above monomeric derivatives of tacrine, Pang and coworkers disclosed a series of bis-tacrines as highly potent and selective inhibitors (2a,b) of AChE (Pang, Y. P. et al., J. Biol. Chem. 1996, 271, 23646-23649). These bis-tacrines were up to 10,000-fold more selective and 1,000-fold more potent than tacrine in inhibiting rat AChE.
All these studies indicate that tacrine may be improved for it selectivity and potency. Based on the above findings, we are disclosing a series of innovative tacrine derivatives for the treatment of Alzheimer's disease.